Citation: Gxaba, N.; Manganyi, M.C.

The Fight against Infection and Pain:

Devil’s Claw (Harpagophytum

procumbens) a Rich Source of

Anti-Inflammatory Activity:

2011–2022. Molecules 2022, 27, 3637.

https://doi.org/10.3390/

molecules27113637

Academic Editors: Guy P.P. Kamatou

and Hinanit Koltai

Received: 14 March 2022

Accepted: 30 May 2022

Published: 6 June 2022

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molecules

Review

The Fight against Infection and Pain: Devil’s Claw(Harpagophytum procumbens) a Rich Source ofAnti-Inflammatory Activity: 2011–2022Nomagugu Gxaba and Madira Coutlyne Manganyi *

Department of Biological and Environmental Sciences, Faculty of Natural Sciences, Walter Sisulu University,PBX1, Mthatha 5117, South Africa; ngxaba@wsu.ac.za* Correspondence: mmanganyi@wsu.ac.za or madiramanganyi@gmail.com; Tel.: +27-47-502-2361

Abstract: Harpagophytum procumbens subsp. procumbens (Burch.) DC. ex Meisn. (Sesame seed Family—Pedaliaceae) is a popular medicinal plant known as Devil’s claw. It is predominantly distributedwidely over southern Africa. Its impressive reputation is embedded in its traditional uses as anindigenous herbal plant for the treatment of menstrual problems, bitter tonic, inflammation febrifuge,syphilis or even loss of appetite. A number of bioactive compounds such as terpenoids, iridoidglycosides, glycosides, and acetylated phenolic compounds have been isolated. Harpagoside andharpagide, iridoid glycosides bioactive compounds have been reported in countless phytochemicalstudies as potential anti-inflammatory agents as well as pain relievers. In-depth studies have associ-ated chronic inflammation with various diseases, such as Alzheimer’s disease, obesity, rheumatoidarthritis, type 2 diabetes, cancer, and cardiovascular and pulmonary diseases. In addition, 60%of chronic disorder fatalities are due to chronic inflammatory diseases worldwide. Inflammationand pain-related disorders have attracted significant attention as leading causes of global healthchallenges. Articles published from 2011 to the present were obtained and reviewed in-depth todetermine valuable data findings as well as knowledge gaps. Various globally recognized scientificsearch engines/databases including Scopus, PubMed, Google Scholar, Web of Science, and ScienceDi-rect were utilized to collect information and deliver evidence. Based on the literature results, therewas a dramatic decrease in the number of studies conducted on the anti-inflammatory and analgesicactivity of Devil’s claw, thereby presenting a potential research gap. It is also evident that currentlyin vivo clinical studies are needed to validate the prior massive in vitro studies, therefore deliveringan ideal anti-inflammatory and analgesic agent in the form of H. procumbens products.

Keywords: Devil’s claw; Harpagophytum procumbens; clinical studies; anti-inflammatory; analgesic

1. Introduction

Inflammation is a multifaceted bio-physiological host defense mechanism againstharmful stimuli such as unwanted pathogens, toxic substances and tissue damage [1–6]. Abody of evidence has shown that inflammation has been associated with several diseasesincluding rheumatoid arthritis, asthma, atherosclerosis and osteoarthritis (OA) [7–13].Inflammation drives or modulates several disorders, which have a significant occurrence inpeople around the world [14,15]. Chronic diseases are ranked as some of the biggest risksto human health [16,17]. Pain associated with inflammation is a common signal in responseto tissue injury [18,19]. Moreover, this has attracted significant attention as a leadingcause of global health challenges [20]. Pain as an advanced stage of inflammation is anunpleasant sensation that signals successive nerve fibers and conscious sensitivity [21,22].Currently, most nonsteroidal anti-inflammatory drugs (NSAIDs) are expensive and maylead to side-effects such as progressive heart failure, gastrointestinal lesions, and renaland liver failure [23–25]. In order to ameliorate the side effects, researchers have shiftedtowards various natural alternatives.

Molecules 2022, 27, 3637. https://doi.org/10.3390/molecules27113637 https://www.mdpi.com/journal/molecules

Molecules 2022, 27, 3637 2 of 18

Inflammation and pain-related disorders possess a global health challenge. Acrossevolutionary adaptation time, inflammation is a physiological host defense mechanism toharmful stimuli such as tissue damage, unwanted pathogens, toxic substances and evenirradiation [18]. The primary aim of inflammation is to prevent the spread of infectionand to begin the recovery process. In addition, tissue homeostasis will be restored byhealing and regeneration of tissues; hence returning to a normal structural and functionalcondition. Usually, inflammation is categorized into acute and chronic inflammation basedon distinctive pathways. Numerous studies have reported that chronic inflammationis associated with several diseases, such as Alzheimer’s disease, obesity, rheumatoidarthritis, type 2 diabetes, cancer, and cardiovascular and pulmonary diseases. Currently,an overwhelming 60% of chronic disorder fatalities are a result of chronic inflammatorydiseases worldwide [15]. Chronic diseases are ranked as some of the biggest risks to humanhealth [16,17]. Pain associated with inflammation is a common signal in response to tissueinjury. Inflammation and pain-related disorders have attracted significant attention asleading causes of global health challenges, hence the continued pursuance of an idealnatural anti-inflammatory agent.

For many years, ethnobotanical practices of native South Africans have become anintegral part of the country’s healthcare system with an uninterrupted historic use [19]. Insuch a developing country, the majority of the population utilizes medicinal plants for theirprimary healthcare needs, thus reducing the overwhelmed, high-cost modern healthcaresystem. This has sparked interest in medicinal plant research since the global megatrendis towards a sustainable, eco-friendly, greener, and healthier lifestyle. One such valuableplant is Harpagophytum procumbens subsp. procumbens (Burch.) DC. ex Meisn. Historically,the native Khoisan people have harvested and utilized the Devil’s claw (Harpagophytumprocumbens) for childbirth, loss of appetite, and as a purgative, as well as the treatmentof various diseases and ailments such as menstrual problems, indigestion, bitter tonic,inflammation febrifuge and syphilis [26,27].

The Harpagophytum genus is widely identified as Devil’s claw belonging to the sesameseed family, Pedaliaceae which is a family of 22 genera with 90 species [28]. It is furthercharacterized as a perennial tuberous plant with visually appealing fruits [29]. Manylengthy protrusions with sharp, grapple-like hooks grow spontaneously on the fruitsand along the upper surface with two straight thorns, and so it is aptly named “Devil’sclaw” [30]. However, the name Devil’s claw refers to H. procumbens (Burch.) DC. ex Meisn.and H. zeyheri Decne which are closely related species [31]. In addition, Devil’s claw(H. procumbens) as a traditional medicinal plant is popular for its wide range of medicinalapplications. It is native to Southern Africa particularly; South Africa, Namibia, Botswana,Angola, Zambia, Zimbabwe, and Mozambique [32].

Expanding on the above, topical application of Devil’s claw ointment has been usedfor the treatment of boils, sprains, and sores, as well as to ease childbirth [31]. It has beenused both internally and externally as a bitter tonic and for its anti-inflammatory qualities.An extensive range of secondary bioactive compounds from Devil’s claw have been iden-tified, such as amino acids, carbohydrates, iridoids, flavonoids, and phytosterols [30,33].Findings from drug product development reveal that terpenoids, iridoid glycosides, gly-cosides and acetylated phenolic extracted from tubers of Devil’s claw were utilized inthe manufacture of drugs [34]. Several studies have shown Devil’s claw as an excellentsource of anti-inflammatory, antibacterial, antifungal, antiviral and anticancer therapeuticproperties. Scientific research also established that Devil’s claw has more advantageousbenefits when compared to non-steroidal anti-inflammatory drugs (NSAIDs), in fact, it is abetter alternative treatment [35,36]. It is evident from previous research findings on thisplant that it was utilized as a remedy for inflammatory conditions, and it has pain-relievingproperties for the treatment of degenerative painful rheumatic conditions.

Furthermore, the herbal plants have been utilized for indigestion, blood diseases,fevers, sprains and rheumatic conditions [37]. The plant has been promoted as a foodsupplement for degenerative arthritis conditions [38]. Considering the number of research

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papers demonstrating the various biological activities of Harpagophytum procumbens (Devil’sclaw); the next logical step should be the investigations using animal studies, as well ashuman trials with negative control parameters. Therefore, this paper provides a compre-hensive systematic summary of current studies (published in 2011–present) conductedon the anti-inflammatory properties, bioactive compounds, and safety profiles of Devil’sclaw for pain-relieving properties and for the treatment of degenerative painful rheumaticconditions as described in Sections 3.6 and 3.7.

2. Methodology

The present literature review was compiled by systematically collecting, reviewing,and assembling current (2011 to present) information from globally recognized electronicdatabases such as Google Scholar, Scopus, Web of Science, PubMed and ScienceDirect.This comprehensive search was conducted using keywords (Devil’s claw; Harpagophy-tum procumbens; Clinical Studies; Biological activities; Safety; in vivo). In addition, wepre-screened the abstracts before studying the full documents. The literature review wasanalysed in-depth to acquire new insights and knowledge gaps for prospective researchopportunities. The current review covers only one subspecies particularly subsp. procum-bens and throughout the review Harpagophytum procumbens subsp. procumbens (Burch.) wasreferred to as Harpagophytum procumbens.

3. Results

Various search engines were utilized to extrapolate 996 articles from Google Scholar, 53from Scopus, 14 from PubMed, 7 from Web of Science and 47 from Science Direct. Amongthese, only articles published in English between 2011 and 2022 were selected accordingto the inclusion/exclusion parameters in Figure 1. A preliminary screening of titles andabstracts was conducted to omit any irrelevant studies, followed by a full text review andanalysis. This body of research provides significant information from the main findingsover the past ten years and explores the changes, gaps, and future prospects.

Molecules 2022, 27, x FOR PEER REVIEW 3 of 19

Furthermore, the herbal plants have been utilized for indigestion, blood diseases, fe-vers, sprains and rheumatic conditions [37]. The plant has been promoted as a food sup-plement for degenerative arthritis conditions [38]. Considering the number of research papers demonstrating the various biological activities of Harpagophytum procumbens (Devil’s Claw); the next logical step should be the investigations using animal studies, as well as human trials with negative control parameters. Therefore, this paper provides a comprehensive systematic summary of current studies (published in 2011–present) con-ducted on the anti-inflammatory properties, bioactive compounds, and safety profiles of Devil’s Claw for pain-relieving properties and for the treatment of degenerative painful rheumatic conditions as described in Section 3.7 and 3.8.

2. Methodology The present literature review was compiled by systematically collecting, reviewing,

and assembling current (2011 to present) information from globally recognized electronic databases such as Google Scholar, Scopus, Web of Science, PubMed and ScienceDirect. This comprehensive search was conducted using keywords (Devil’s Claw; Harpagophytum procumbens; Clinical Studies; Biological activities; Safety; in vivo). In addition, we pre-screened the abstracts before studying the full documents. The literature review was ana-lysed in-depth to acquire new insights and knowledge gaps for prospective research op-portunities. The current review covers only one subspecies particularly subsp. procumbens and throughout the review Harpagophytum procumbens subsp. procumbens (Burch.) was re-ferred to as Harpagophytum procumbens.

3. Results Various search engines were utilized to extrapolate 996 articles from Google Scholar,

53 from Scopus, 14 from PubMed, 7 from Web of Science and 47 from Science Direct. Among these, only articles published in English between 2011 and 2022 were selected ac-cording to the inclusion/exclusion parameters in Figure 1. A preliminary screening of titles and abstracts was conducted to omit any irrelevant studies, followed by a full text review and analysis. This body of research provides significant information from the main find-ings over the past ten years and explores the changes, gaps, and future prospects.

Figure 1. Inclusion and exclusion criteria on the systematic literature search.

3.1. Botanical Description of Harpagophytum procumbens Harpagophytum procumbens (Devil’s Claw) is one of the medicinally and economically

important members of the sesame seed family, Pedaliaceae [39]. It is a weedy, perennial, tuberous plant with a conspicuous fruit [40]. The fruit is the one that gave this plant its colloquial name ‘Devil’s Claw’ [26,41]. The fruit is a woody capsule of varying sizes with long protruding sharp, grapple-like hooks [30]. Inside the fruit are numerous seeds in rows of four in each loculus and these are dispersed over a long period of time. It has creeping, annual stems that grow to a height of 2 m from a tuberous fleshy rootstock [41].

Figure 1. Inclusion and exclusion criteria on the systematic literature search.

3.1. Botanical Description of Harpagophytum procumbens

Harpagophytum procumbens (Devil’s claw) is one of the medicinally and economicallyimportant members of the sesame seed family, Pedaliaceae [39]. It is a weedy, perennial,tuberous plant with a conspicuous fruit [40]. The fruit is the one that gave this plant itscolloquial name ‘Devil’s claw’ [26,41]. The fruit is a woody capsule of varying sizes withlong protruding sharp, grapple-like hooks [30]. Inside the fruit are numerous seeds in rowsof four in each loculus and these are dispersed over a long period of time. It has creeping,annual stems that grow to a height of 2 m from a tuberous fleshy rootstock [41]. This stemhas hollow branches which are covered with glandular hairs that exude slimy, sticky sap.This stem sprouts from a succulent taproot [11].

The creeping nature of the stem is what gave this plant its species name procumbens.From the succulent tap root, thick secondary roots branch off horizontally. These secondary

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tubers are 25 cm long with 6 cm thickness. The particular secondary roots are the therapeuticpart of the plants as they consist of between 0.5 and 3% of iridoid glycosides [30,42]. Theleaves are borne on opposite sides of the trailing stem, and they are irregularly divided into3–5 lobes while being greyish-green in colour because of the tiny whitish mucilage cellscovering them as shown in Figure 2A. The flowers are tubular shaped with a color rangingfrom dark velvety red or purple to pink a simple, opposite, and oval in shape while thetube base and mouth are yellowish to white. They open during the day to allow pollinationby bees [41]. The genus Harpagophytum consists of two related species procumbens andzeyheri [28,29]. Of the two species, H. procumbens is considered to be more medicinallyefficient than H. zeyheri. The superiority of H. procumbens over H. zeyheri was attributed tothe presence of higher chemical constituents in H. procumbens [30]. This has led to medicinalproduct(s) derived from it being sold as one or the other or mixed [28].

It was then proposed that the two species be turned apart as this mix-up was foundto lower the quality of the intended medical drug [30]. The two species were then dis-tinguished based on fruit capsule seed rows. In H. procumbens, the fruit capsule has fourseed rows whereas that of H. zeyheri has two [40]. This way of distinguishing the twospecies of Harpagophytum was not effective because the seed numbers were not restrictedto four or two as there might have been introgression between the two species [41]. Theother distinguishing feature of these species was the appearance of the fruit capsule. Thefruit capsule in H. procumbens usually has three long arms while that of H. zeyheri haseight short arms with slightly curved arms at the tips [41]. However, this distinctionwas also not sufficient, particularly at harvest time. Once the tubers are harvested, thedistinction between the tubers was virtually impossible. Mncwangi et al. [43] comparedthe chemical composition of the two species and found that they were not comparable.This chemical composition still confirmed that H. procumbens was still superior to H. zeyheri.The name Harpagophytum came from the Greek word ‘harpago’ which means ‘grapplinghook’ [44,45]. There are several common names that have been given to this plant theseinclude Devil’s claw, grapple plant, wood (Teufffelskralle), Trampelklette (German), Griffedu diable (French) (Kempel).

Molecules 2022, 27, x FOR PEER REVIEW 4 of 19

This stem has hollow branches which are covered with glandular hairs that exude slimy, sticky sap. This stem sprouts from a succulent taproot [11].

The creeping nature of the stem is what gave this plant its species name procumbens. From the succulent tap root, thick secondary roots branch off horizontally. These second-ary tubers are 25 cm long with 6 cm thickness. The particular secondary roots are the ther-apeutic part of the plants as they consist of between 0.5 and 3% of iridoid glycosides [30,42]. The leaves are borne on opposite sides of the trailing stem, and they are irregularly divided into 3–5 lobes while being greyish-green in colour because of the tiny whitish mucilage cells covering them as shown in Figure 2A. The flowers are tubular shaped with a color ranging from dark velvety red or purple to pink a simple, opposite, and oval in shape while the tube base and mouth are yellowish to white. They open during the day to allow pollination by bees [41]. The genus Harpagophytum consists of two related species procumbens and zeyheri [28,29]. Of the two species, H. procumbens is considered to be more medicinally efficient than H. zeyheri. The superiority of H. procumbens over H. zeyheri was attributed to the presence of higher chemical constituents in H. procumbens [30]. This has led to medicinal product(s) derived from it being sold as one or the other or mixed [28].

It was then proposed that the two species be turned apart as this mix-up was found to lower the quality of the intended medical drug [30]. The two species were then distin-guished based on fruit capsule seed rows. In H. procumbens, the fruit capsule has four seed rows whereas that of H. zeyheri has two [40]. This way of distinguishing the two species of Harpagophytum was not effective because the seed numbers were not restricted to four or two as there might have been introgression between the two species [41]. The other distinguishing feature of these species was the appearance of the fruit capsule. The fruit capsule in H. procumbens usually has three long arms while that of H. zeyheri has eight short arms with slightly curved arms at the tips [41]. However, this distinction was also not sufficient, particularly at harvest time. Once the tubers are harvested, the distinction between the tubers was virtually impossible. Mncwangi et al. [43] compared the chemical composition of the two species and found that they were not comparable. This chemical composition still confirmed that H. procumbens was still superior to H. zeyheri. The name Harpagophytum came from the Greek word ‘harpago’ which means ‘grappling hook’ [44,45]. There are several common names that have been given to this plant these include Devil’s Claw, grapple plant, wood (Teufffelskralle), Trampelklette (German), Griffe du diable (French) (Kempel).

Figure 2. Harpagophytum procumbens (Devil’s Claw) (A) Devil’s Claw plant with pink flowers (SANBI) [44]; (B) H. procumbens tubers; (C) Dried H. procumbens sliced tubers used for plant extracts [27] (D) Devil’s Claw (SANBI) [45].

Figure 2. Harpagophytum procumbens (Devil’s claw) (A) Devil’s claw plant with pink flowers(SANBI) [44]; (B) H. procumbens tubers; (C) Dried H. procumbens sliced tubers used for plant ex-tracts [27] (D) Devil’s claw (SANBI) [45].

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3.2. Traditional Uses of Harpagophytum procumbens as Bases of Investigation

For centuries, the first inhabitants of Southern Africa, also well known as the indige-nous “Khoisan” people, utilized Devil’s claw in ancient prescriptions for various healthconditions [11,26]. The high influx of immigration from other African tribes includingBantu-speaking people brought about the exchange of traditional knowledge systems [46].The arrival of Europeans in South Africa was no exception, Devil’s claw tubers were tradedto Germany in 1962 [28]. As the years progressed, various herbal formulations such aspowders, infusions, tinctures, extracts, and decoctions have been prepared from Harpago-phytum procumbens root tubers [47]. Harpagophytum procumbens remedies are an excellentsource of topical medicines. For these uses, the tubers were collected in the wild, sliced,dried, and made into tea [48,49]. They have also been used as a topical treatment for burntwounds, sprains, sores, boils, and other skin problems [30]. As a topical treatment, the rootis dried and powdered and directly used to cover wounds; or the powdered root is mixedwith animal fat or petroleum jelly to make an ointment that effectively treats muscularaches and pains, and painful joints [11]. However, there has not been definitive scientificevidence to substantiate the effective use of the Devil’s claw as an ointment [31].

It was regarded to be a therapeutic pain reliever as well as treating arthritis. Inaddition, Devils claw has been utilized for treating a large selection of conditions, includingurinary tract infections, sores, fever, dyspepsia, blood diseases, postpartum pain, sprains,and ulcers [50]. Due to its anti-inflammatory and analgesic effects, the use of H. procumbenshas spread to other countries, United Kingdom, Holland, the United States and the FarEast where it is registered as a food supplement for degenerative arthritic conditions, inGermany and France it is an important herbal medicine [26]. In Brazil, H. procumbensis released as herbal medicine (by the National Surveillance Agency, ANVISA) used forthe relief of mild joint pain and acute back pain [32]. Harpagophytum procumbens in thesehealth conditions is used in the formulations of an infusion, decoction, tincture, powder,and extract [30]. The utilization of Harpagophytum procumbens has the function of a mildlaxative, small quantities alleviate menstrual cramps although higher quantities aid inexpelling retained placentas. One of the earliest ethnobotany records was Samuel Karikousing Devil’s claw to combat constipation, cough, diarrhea, and venereal infections.

The secondary tuber of Harpagophytum procumbens is dried and pulverized into pow-dered form and used externally for dressing wounds and sometimes infused with animalfat or Vaseline®® to produce a wound- and burn-healing ointment [11,51]. Harpagophytumprocumbens is also used to treat digestive problems, diabetes, as a tonic herb and infectiousailments [52,53]. A liquid decoction of the H. procumbens secondary tubers or chewing itmight result in stomach and postpartum pain relief, as previously reported by the Topnaarpeople of Namibia [54]. Furthermore, H. procumbens infusions have therapeutic effects for‘blood diseases’ and as a bitter tonic [55]. With emerging ailments and/or diseases on therise, H. procumbens has been reported to alleviate asthma, pancreatitis, tuberculosis, andfor treating liver diseases, syphilis, rheumatism, kidney diseases and gonorrhea [11]. Ina cleansing ceremony, an ancient practice, the Devil’s claw secondary tubers are mixedwith Asparagus or Protasparagus roots and used to cover the cuts on the skin [51]. Theethnobotanical accounts gathered have been from the earliest records and solidify the basisfor an H. procumbens investigation.

3.3. Phytochemistry of Harpagophytum procumbens

The phytochemical studies of H. procumbens have revealed that the main chemical con-stituents that have been thought to reduce inflammation in this herb are iridoid glycosides(IG), phenolic glycosides such as acteoside, isoacteoside and bioside, harpagoquinones,amino acids, phenolic (aromatic) acids (caffeic, cinnamic and chlorogenic aicds), flavonoids,phytosterols and carbohydrates (turanose and starchyose) as bioactive compounds of thisplants [30,33,38]. Iridoid glycosides are a large group of compounds belonging to a classmonoterpene derived from geraniol with a general form of cyclopentopyran although, incertain instances, the ring is cleaved and forms secologanin [56]. Iridoid glycosides are a

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massive group of compounds in H. procumbens with high concentrations of harpagosideh,arpagide, procumbide, procombiside 8-O-(p-Coumaroyl)-harpagide, and harpagogenineas shown Figure 3 [30,57]. These compounds were isolated in tuber roots and are believedto exhibit anti-inflammatory as well as analgesic properties [58]. The first iridoid glycosideto be isolated in 1962 by a scientist from W

Molecules 2022, 27, x FOR PEER REVIEW 6 of 19

longing to a class monoterpene derived from geraniol with a general form of cyclopento-pyran although, in certain instances, the ring is cleaved and forms secologanin [56]. Iri-doid glycosides are a massive group of compounds in H. procumbens with high concentra-tions of harpagosideh, arpagide, procumbide, procombiside 8-O-(p-Coumaroyl)-harp-agide, and harpagogenine as shown Figure 3 [30,57]. These compounds were isolated in tuber roots and are believed to exhibit anti-inflammatory as well as analgesic properties [58]. The first iridoid glycoside to be isolated in 1962 by a scientist from W ϋ rzburg was harpagoside. Among the iridoid glycosides, harpagoside is the most investigated and is considered a reference standard for titration purposes [38]. It is believed that a single chemical constituent cannot carry out the bioactivity, hence, the contribution of several active compounds is required. This might explain the findings that harpagoside was not an efficient anti-inflammatory agent. The chemical structures of these iridoid glycosides were elucidated using nuclear magnetic resonance (NMR) spectroscopy [59]. Studies have shown that H. procumbens root tuber extracts that inhibited inflammation and alleviated pain contained harpagide [60], harpagoside, 8-p-coumaroylharpagide and acteoside as the main bioactive compounds [30,34]. From these results, it was concluded that the effi-cacy of the extract is dependent on the presence of the active agents. Interestingly, an ex-tract free of harpagoside also exhibited marked inhibition of inducible NO synthase ex-pression, however, pure harpagoside exerted strong antioxidant activity [61,62].

rzburg was harpagoside. Among the iridoidglycosides, harpagoside is the most investigated and is considered a reference standard fortitration purposes [38]. It is believed that a single chemical constituent cannot carry out thebioactivity, hence, the contribution of several active compounds is required. This mightexplain the findings that harpagoside was not an efficient anti-inflammatory agent. Thechemical structures of these iridoid glycosides were elucidated using nuclear magnetic reso-nance (NMR) spectroscopy [59]. Studies have shown that H. procumbens root tuber extractsthat inhibited inflammation and alleviated pain contained harpagide [60], harpagoside,8-p-coumaroylharpagide and acteoside as the main bioactive compounds [30,34]. Fromthese results, it was concluded that the efficacy of the extract is dependent on the presenceof the active agents. Interestingly, an extract free of harpagoside also exhibited markedinhibition of inducible NO synthase expression, however, pure harpagoside exerted strongantioxidant activity [61,62].

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longing to a class monoterpene derived from geraniol with a general form of cyclopento-pyran although, in certain instances, the ring is cleaved and forms secologanin [56]. Iri-doid glycosides are a massive group of compounds in H. procumbens with high concentra-tions of harpagosideh, arpagide, procumbide, procombiside 8-O-(p-Coumaroyl)-harp-agide, and harpagogenine as shown Figure 3 [30,57]. These compounds were isolated in tuber roots and are believed to exhibit anti-inflammatory as well as analgesic properties [58]. The first iridoid glycoside to be isolated in 1962 by a scientist from Wϋrzburg was harpagoside. Among the iridoid glycosides, harpagoside is the most investigated and is considered a reference standard for titration purposes [38]. It is believed that a single chemical constituent cannot carry out the bioactivity, hence, the contribution of several active compounds is required. This might explain the findings that harpagoside was not an efficient anti-inflammatory agent. The chemical structures of these iridoid glycosides were elucidated using nuclear magnetic resonance (NMR) spectroscopy [59]. Studies have shown that H. procumbens root tuber extracts that inhibited inflammation and alleviated pain contained harpagide [60], harpagoside, 8-p-coumaroylharpagide and acteoside as the main bioactive compounds [30,34]. From these results, it was concluded that the effi-cacy of the extract is dependent on the presence of the active agents. Interestingly, an ex-tract free of harpagoside also exhibited marked inhibition of inducible NO synthase ex-pression, however, pure harpagoside exerted strong antioxidant activity [61,62].

Figure 3. Chemical structures of the major iridoids glycosides and phenylethanoid from H. procum-bens [45].

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Phenolic glycoside refers to any molecule with a sugar unit attached to a phenolaglycone in a general sense [63].

Phenolic glycosides have been indicated in the therapy of inflammatory diseases [64].The phenolic glycosides that have been identified in H. procumbens are 8- feruloyharpagide,verbascoside, leuxosceptoside, pagoside, illustrated in Figure 4A–C [65]. Among these,verbascoside, also known as acteoside, was found to have a strong anti-inflammatory effectwhich was either comparable or even higher than that of harpagoside [66]. The other phe-nolic glycosides of H. procumbens either have a strong antioxidant activity or antimicrobialactivities [43]. Orally administered amino acids such as glycine, lysine, L- proline andvaline have exhibited anti-inflammatory activities in some tests [67]. Amino acids found inplants have been reported to exhibit anti-inflammatory activity [68]. The minor chemicalconstituents of H. procumbens such as flavonoids (kaempferol and luteolin) and phenolic oraromatic acids (such as cinnamic, caffeic and chloronic acids, Figure 4A,B) have also beenreported to exert some anti-inflammatory abilities [43]. Flavonoids were isolated using phy-tochemical screening and confirmed with 1D NMR spectra in these plants [69]. Terpenoids,ursolic, oleanolic acid and beta-sitosterol were the other minor chemical constituents of H.procumbens that have been found to have anti-inflammatory effects. The isolation of thesechemical constituents from other plant parts has been considered laborious and can hinderpharmacological studies [47].

Molecules 2022, 27, x FOR PEER REVIEW 7 of 19

Figure 3. Chemical structures of the major iridoids glycosides and phenylethanoid from H. procum-bens [45].

Phenolic glycoside refers to any molecule with a sugar unit attached to a phenol agly-cone in a general sense [63].

Phenolic glycosides have been indicated in the therapy of inflammatory diseases [64]. The phenolic glycosides that have been identified in H. procumbens are 8- feruloyharp-agide, verbascoside, leuxosceptoside, pagoside, illustrated in Figure 4A–C [65]. Among these, verbascoside, also known as acteoside, was found to have a strong anti-inflamma-tory effect which was either comparable or even higher than that of harpagoside [66]. The other phenolic glycosides of H. procumbens either have a strong antioxidant activity or antimicrobial activities [43]. Orally administered amino acids such as glycine, lysine, L- proline and valine have exhibited anti-inflammatory activities in some tests [67]. Amino acids found in plants have been reported to exhibit anti-inflammatory activity [68]. The minor chemical constituents of H. procumbens such as flavonoids (kaempferol and luteo-lin) and phenolic or aromatic acids (such as cinnamic, caffeic and chloronic acids, Figure 4A,B) have also been reported to exert some anti-inflammatory abilities [43]. Flavonoids were isolated using phytochemical screening and confirmed with 1D NMR spectra in these plants [69]. Terpenoids, ursolic, oleanolic acid and beta-sitosterol were the other mi-nor chemical constituents of H. procumbens that have been found to have anti-inflamma-tory effects. The isolation of these chemical constituents from other plant parts has been considered laborious and can hinder pharmacological studies [47].

Figure 4. Chemical structure of the phenolics; phenolic glycosides of H. procumbens [29].

3.4. Anti-Inflammatory Properties of Harpagophytum procumbens The Harpagophytum procumbens ethanol extract (60% v/v ethanol) reduced the COX-2

mRNA quantity in a dose-dependent manner at 50 μg/mL and 200 μg/mL(Figure 5). The Harpagophytum extract was Pascoe®®-Agil 240 mg, film-coated tablets. The transcription

Figure 4. Chemical structure of the phenolics; phenolic glycosides of H. procumbens [29].

Molecules 2022, 27, 3637 8 of 18

3.4. Anti-Inflammatory Properties of Harpagophytum procumbens

The Harpagophytum procumbens ethanol extract (60% v/v ethanol) reduced the COX-2mRNA quantity in a dose-dependent manner at 50 µg/mL and 200 µg/mL(Figure 5).The Harpagophytum extract was Pascoe®®-Agil 240 mg, film-coated tablets. The transcrip-tion factor activator protein 1 (AP-1) activity was reduced in murine macrophages andcytokine expression. Similarly, TNF-α and interleukin 6 (IL-6) were suppressed at concen-trations of 100 µg/mL and 200 µg/mL, respectively. The results also showed the mostanti-inflammatory potential of Harpagophytum procumbens extract (IC50) at 100 mg/mLand lower [39]. Harpagoside and harpagide, which are monoterpenoids commonlyfound in Harpagophytum procumbens, have been shown to inhibit TNFα-secretion in PMA-differentiated THP-1 cells. Subsequently, mRNA expression belonging to a particularprotein in leukocyte transmigration was induced. After 48 h, the expression was retainedon high concentrations and strong induction of L-selectin and PSGL-1 of stimulation.Within 3 h, there was a positive impact on TNFα and ICAM-1 mRNA expression. Thesefindings indicate that cell movement into the swollen tissue is due to the harpagosideand harpagide showing their immune-modulatory role and resident macrophages wereelevated indicating a potentially effective anti-inflammatory agent [70].

Molecules 2022, 27, x FOR PEER REVIEW 9 of 19

a study conducted by Cock and Bromley [75], H. procumbens root tuber extracts were shown to be effective bacterial trigger inhibitors of autoimmune inflammatory diseases [75]. In a most recent study, a randomized triple-blind placebo-control trial was conducted on runners with self-reported knee pain using H. procumbens combined with other medic-inal plants as an analgesic and anti-inflammatory agent. The database on the study showed a significant reduction in leg fat mass (p = 0.037) and knee thermograms noticeable in IG (p < 0.05). No differences were found in the overall safety and the efficacy of H. procumbens mixtures as an anti-inflammatory nutritional supplement [76]. Mariano et al. [38] investigated the antiarthritic properties of H. procumbens root extract and molecular mechanisms, as well as bioactive compounds. Interestingly, the expression of the Canna-binoid receptor 2 (CB2) receptor was enhanced by certain bioactive compounds, however, it was unexpressed in the osteoarthritic tissues. Chronic inflammation has been recog-nized as a variable mediator of osteoarthritis. Several studies have reported that CB 2 re-ceptors are expressed as an immune response and display an inflammatory effect [77–80].

Figure 5. Number of research papers on Harpagophytum spp., 1822–2021 (publication lan-guage/origin of research) [28].

3.5. Analgesic Effects of Harpagophytum procumbens Current synthetic drugs used for the management of analgesia have been expensive

as well as ineffective. These drugs have been associated with numerous adverse effects, hence the endless pursuance of substitute sources. For centuries, native tribes across the world have used medicinal plants for therapeutic pain relief, and nowadays this has gained attraction in the research as well as pharmaceutical sectors [3,13,81,82]. Parenti et al. [21], administered several combinations of H. procumbens extract with morphine via in vivo trials using rats. The rats were induced with chronic constriction injury (CCI) as neu-ropathic pain. The data suggested a synergistic result of the combination of H. procumbens and morphine. Furthermore, the combination acts as an excellent pain reliever, as well as reduces the side effects related to neuropathic pain [21]. In a recent study, a cream formu-lation was prepared from H. procumbens root extract for the treatment of neck/shoulder sport-related pains. The treatment was administrated on the skin of healthy participants. After 2 weeks, the pain subsided and the participants reported a boost in strength, mobil-ity and working abilities [83].

In a Cochrane review [84], daily quantities of H. procumbens with 50 mg or 100 mg harpagoside administrated to participants improved the pain. While other reports showed the effectiveness of lesser doses of H. procumbens in a smaller trial group [84].

Figure 5. Number of research papers on Harpagophytum spp., 1822–2021 (publication language/originof research) [28].

Hostanska et al. [71] also demonstrated the anti-inflammatory activity of Devil’s clawtuber extracts by an external metabolic activation and the discharge of proinflammatorycytokines. The results showed no significant metabolic activation of the extract mixture S9mixture (S9 mix homogenate blended with 60% ethanol H. procumbens extract) with no cyto-toxic and inhibition activities. However, TNF-α demonstrated potential anti-inflammatoryactivity with EC50 concentration levels of 116 ± 8.2 µg/mL and 49 ± 3.5 µg/mL for DCand DCM (p < 0.01), respectively. TNF-α, IL-6 and IL-8 dose-dependently were inhibitedin monocytic THP-1 cells treated with LPS at non-cytotoxic doses (50–250 µg/mL). Thecytokines’ effect was not influenced by metabolic activation, interestingly, even though wealso found that the concentration of harpagoside and caffeic acid derivates was reduced.The anti-inflammatory potential of harpagoside and harpagide was studied by structuralmolecular biology and computer-assisted drug design, molecular docking. However,evidence suggests that harpagoside and harpagide affect COX-2, with binding energiesestimated at −9.13 and −5.53 kcal/mol, respectively. The stabilization of harpagosideand harpagide occurred at the active site of COX-2 through 7 and 10 hydrogen bonds,

Molecules 2022, 27, 3637 9 of 18

respectively. It can be concluded that harpagoside and harpagide are promising leads foradditional study as potential anti-inflammatory/analgesic compounds; highly selectiveCOX-2 inhibitors. They might provide a safer more effective anti-inflammatory/analgesicagency than the currently commercialized non-steroidal anti-inflammatory drugs [72].

An ex vivo rat colon model has demonstrated the anti-inflammatory activity of H.procumbens root tuber extracts in multiple tissues and ultimately provides a therapeuticalternative to inflammatory diseases [54]. In another study, Gyurkovska and colleagues [67],reported that several H. procumbens root extracts exhibited excellent anti-inflammatoryactivities in vitro systems. Murine macrophages displayed the release of nitric oxide (NO)and cytokine (TNF-α, IL-6) and the expression of COX-1 and COX-2 [67]. There is nowcompelling evidence that harpagoside, a natural compound from Devil’s claw, has beenshown to possess anti-inflammatory activities. In a mouse model, harpagoside suppressedinflammation-induced bone loss while preventing the receptor activator of nuclear factorκB ligand (RANKL)-induced osteoclastogenesis. Furthermore, harpagoside prevented thedevelopment of osteoclasts from mouse bone marrow macrophages dose-dependently.In the same content, it reduced extracellular signal-regulated kinase (ERK) and c-jun N-terminal kinase (JNK) phosphorylation, resulting in the prevention of Syk-Btk-PLCγ2-Ca2+in RANKL-dependent early signaling [73]. In addition, harpagoside also demonstratedits ability to suppress c-FOS functioning as AP-1 transcription factors in osteoarthritischondrocytes [62].

In another study, H. procumbens ethanol extracts from the whole plant, as well as othermedicinal plants, were subjected to anti-denaturation action in heat-treated Bovine SerumAlbumin (BSA), as a function of anti-inflammatory compounds. The dose-dependentresults showed the inhibition of protein (albumin) denaturation at concentrations of50–1000 µg/mL. H. procumbens demonstrated good anti-inflammatory properties [74].In a study conducted by Cock and Bromley [75], H. procumbens root tuber extracts wereshown to be effective bacterial trigger inhibitors of autoimmune inflammatory diseases [75].In a most recent study, a randomized triple-blind placebo-control trial was conducted onrunners with self-reported knee pain using H. procumbens combined with other medicinalplants as an analgesic and anti-inflammatory agent. The database on the study showeda significant reduction in leg fat mass (p = 0.037) and knee thermograms noticeable in IG(p < 0.05). No differences were found in the overall safety and the efficacy of H. procumbensmixtures as an anti-inflammatory nutritional supplement [76]. Mariano et al. [38] investi-gated the antiarthritic properties of H. procumbens root extract and molecular mechanisms,as well as bioactive compounds. Interestingly, the expression of the Cannabinoid receptor 2(CB2) receptor was enhanced by certain bioactive compounds, however, it was unexpressedin the osteoarthritic tissues. Chronic inflammation has been recognized as a variable medi-ator of osteoarthritis. Several studies have reported that CB 2 receptors are expressed as animmune response and display an inflammatory effect [77–80].

3.5. Analgesic Effects of Harpagophytum procumbens

Current synthetic drugs used for the management of analgesia have been expensiveas well as ineffective. These drugs have been associated with numerous adverse effects,hence the endless pursuance of substitute sources. For centuries, native tribes across theworld have used medicinal plants for therapeutic pain relief, and nowadays this has gainedattraction in the research as well as pharmaceutical sectors [3,13,81,82]. Parenti et al. [21],administered several combinations of H. procumbens extract with morphine via in vivo trialsusing rats. The rats were induced with chronic constriction injury (CCI) as neuropathic pain.The data suggested a synergistic result of the combination of H. procumbens and morphine.Furthermore, the combination acts as an excellent pain reliever, as well as reduces theside effects related to neuropathic pain [21]. In a recent study, a cream formulation wasprepared from H. procumbens root extract for the treatment of neck/shoulder sport-relatedpains. The treatment was administrated on the skin of healthy participants. After 2 weeks,

Molecules 2022, 27, 3637 10 of 18

the pain subsided and the participants reported a boost in strength, mobility and workingabilities [83].

In a Cochrane review [84], daily quantities of H. procumbens with 50 mg or 100 mgharpagoside administrated to participants improved the pain. While other reports showedthe effectiveness of lesser doses of H. procumbens in a smaller trial group [84]. Previously,male SD rats were subjected to plantar incision and spared nerve injury (SNI) to determinethe pain-related behavior and H. procumbens was utilized as a treatment. There wasa significant increase in the MWT values of the 300 mg/kg H. procumbens-treated groupfollowed by a decline in the number of 22–27 kHz USVs after 6 h and 24 h of plantar incisionoperation. The 300 mg/kg dose treatment of H. procumbens extracts prepared from thewhole plant displayed continuous improvement of SNI-induced hypersensitivity responsesby MWT after 21 days. The study recommends the use of H. procumbens extracts as a potentanalgesic agent for the treatment of acute postoperative pain and chronic neuropathicpain [85]. In a traditional healing system, herbal medicine usually consists of more thanone medicinal plant, thus the concoction of formulations. Radomska-Lesniewska et al. [85]supported this hypothesis by preparing Reumaherb concoctions from Harpagophytumprocumbens mixed with two other herbal plants. The study found that oral administration of1.2 mg Reumaherb to mice exhibited potential anti-inflammatory, as well as anti-angiogenic,effects on mononuclear cells. It was, however, concluded the Reumaherb concoctionsshowed excellent concentrations of angiogenesis which might be used for rheumatoidarthritis patients [86].

3.6. Diseases Associated with Inflammation and Pain

Rheumatoid arthritis, by definition, is a chronic inflammatory disorder that mightaffect the lining of joints and induce painful swelling in humans, which can lead to bonedegradation and joint deformity [87,88]. The illness can harm a range of body systemsin some people, including the skin, eyes, lungs, heart, and blood vessels. Osteoarthritis(OA), on the other hand, is defined as a type of articular disease that results from thedegeneration of articular cartilage and subchondral bone [61,89]. It is a common conditionin elderly people [90]. OA is often manifested by joint pain, tenderness, and limitationof movements. Rheumatoid arthritis and osteoarthritis inflammation are managed usingpharmacological and non-pharmacological approaches; the traditional approach targetsthe treatment of symptoms connected to diseases such as pain and physical dysfunction,whereas non-steroidal anti-inflammatory drugs (NSAIDs) have anti-inflammatory andanalgesic effects [21]. Nonetheless, these drugs are very expensive, and they carry substan-tial side effects such as gastrointestinal, cardiovascular, liver and renal complications [85].These adverse effects have forced patients to look for alternative treatments that are effec-tive and safe, such as herbal and nutritive supplements. H. procumbens was introduced asTeltonal, a herbal analgesic that does not only relieve and treat chronic inflammation [21].In vitro studies have revealed that H. procumbens root tuber extracts reduced rheumatoidand osteoarthritis inflammation by suppressing pro-inflammatory mediators such as in-terleukin (IL)-induced production of metalloproteinase [30]. The effectiveness of Devil’sclaw tuber extracts in reducing pain and inflammation caused by rheumatoid arthritis andosteoarthritis has been attributed to the presence of active ingredients [91].

H. procumbens has also been used in the treatment of ulcerative colitis, one of thechronic disorders of the digestive tract [54]. The lining of the colon becomes inflamed,resulting in small open sores or ulcers that generate pus or mucus. Patients suffering fromulcerative colitis show symptoms that vary from mild to widespread inflammation. Theseinclude abdominal discomfort or cramps, rectal bleeding, diarrhoea, anaemia, fatigue,fever, nausea, weight loss, loss of appetite, abdominal sounds, mouth ulcer, loss of bodyfluids and nutrients, skin lesions and growth failure in children [92]. The interest in usingextracts prepared from H. procumbens root tuber was triggered when the administeringof medicines such as 5-amino salicylate, azathioprine, 6-mercaptopurine, cyclosporine,sulfasalazine, and antitumor necrosis factor (TNF)-α inhibitors failed to yield desirable

Molecules 2022, 27, 3637 11 of 18

results [93]. Treatment with these medicines was accompanied by several side effects withsome of them being severe.

Extracts from H. procumbens were prepared with traditional or biocompatible solvents(water and hydroalcoholic solution) to offer efficacious and safe treatments. The extractsreduced inflammation by inhibiting pro-inflammatory mediators such as oxidative stress,5-HT, PGE and 8-iso PGF2α. These effects were found to be comparable with sulfasalazine(2 µg/mL) which was used as a reference drug. The antioxidant and anti-inflammatoryeffects of H. procumbens extracts were ascribed to the following secondary metabolites;harpagoside, gallic acid, catechin, epicatechin, resveratrol, phenolic and flavonoids. Thisextract was also reported to act on bacterial and fungal strains that are often associated withcolon inflammation such as Candida albicans and C. tropicalis. The presence of C. albicansand C. tropicalis in the colon has been reported to aggravate colitis’ clinical symptoms [94].Moreover, a proteomic analysis of the colon that has been treated with H. procumbensextract revealed that there was an up-regulation of the levels of peroxiredoxin-2(PRDX2),glutathione reductase, (GSHR) catalase (CAT), and superoxide dismutase (SOD) which areknown to counteract oxidative stress-induced organ injury [93]. Studies have shown thatthe antioxidant activity of H. procumbens contributes to its anti-inflammatory effect [95]. Ithas been established that H. procumbens extracts also exert anti-inflammatory effects on renalinflammation [26]. Renal inflammation is one of the common problems associated withkidney diseases that have been affecting people these days [96]. Some clinical trial studieshave shown the efficacy of H. procumbens in chronic diseases for human treatment [97], andother studies are summarized in Table 1.

Table 1. Harpagophytum procumbens as an anti-inflammation and pain reliever associated withvarious diseases.

Name of the Disease Disease Symptomsor Complications Part(s) Used Biological Effects of

Devil’s ClawCompoundConstitutes Reference

Alzheimer’s diseaseLoss of memory andcognitive judgment

Dried roots Anti-Alzheimer effect Verbascosidederivatives [98]

Dried rootsManagement of the clinical

symptoms related to ad,inflamed tissues

Harpagoside [99]

Roots Anti-inflammatory activity Phenylethanoidglycoside [62]

Rheumatoid arthritis

Pain associated withjoints, back, or muscles.

Joints are tension,swelling, tenderness,

or weakness

Harpagosidecompound Anti-inflammatory activity Harpagoside [61]

Roots Antiarthritic effects,anti-inflammatory activity Harpagoside [38]

Harpagosidecompound Anti-inflammatory activity Harpagoside [61]

Harpagosidecompound

Antirheumatic effects, painreliever, anti-inflammatory

activityHarpagoside, [100]

Roots Anti-inflammatory activity Harpagoside [101]

OsteoporosisLowered bone pain,

height loss andmuscle spasms.

Plant material Anti-osteoporotic activity Harpagide [102]Plant material Anti-osteoporotic activity Harpagoside [103]Harpagosidecompound Anti-inflammatory Harpagoside [73]

Roots Anti-inflammatory,antioxidant, analgesic Unidentified [20]

Roots Pain reduction and function Unidentified [90]

DiabetesInjury to the large blood

vessels of the heart, brainand legs

Roots Anti-inflammatory andantirheumatic properties Harpagoside [19]

ObesityOverweight, exhaustion,

pot belly, orbreathe heavily

Roots Suppress appetite Iridoid glycosides [104]

Psoriasis Hives, dryness, flakiness,peeling, redness Roots Anti-inflammatory

Phenylethanoidglycosides

verbascoside[51]

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3.7. Safety Aspects of Harpagophytum procumbens

Medicinal plants have been utilized to heal a variety of infectious and non-infectiousailments and/or diseases since ancient times, despite the fact they also exude toxic effects.The toxicity of medicinal plants is affected by several factors such as the exposure time,climate, the potency of bioactive metabolites, various plant parts, genetic variations withinthe species, dosage consumed, soil, and individual body chemistry [16,105]. The litera-ture search has shown the dramatic decline in Harpagophytum procumbens studies and itssafety investigations are no exception. Prior to 2011, there were many studies conductedon the acute and chronic toxicity of Harpagophytum procumbens plant extracts and theirbioactive compounds. Murine peritoneal macrophages and 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) were used to investigate the cytotoxicity of H.procumbens extracts and their purified substances. Compound harpagide demonstratedthe highest toxic result at 1 mg/mL concentration by decreasing the number of viablecells as compared with β-OH-verbascoside and martynoside [66]. In a recent study, Joshiand colleagues [26] conducted a toxicological study of H. procumbens aqueous-alcohol roottuber extract using a rat model. In this model, various doses of H. procumbens extracts wereadministrated to male and female Sprague Dawley rats for a few months (one and threemonths). Histopathology results showed an increased occurrence of heart inflammation inthe control groups as compared to treatment groups. Despite this, there were no detectedhistopathology results due to the intake of the extracts [26].

In another study, acute and chronic toxicity were investigated to detect the effect ofH. procumbens (Devil’s claw) capsules on male and female mice. Some adverse effects suchas the growth of forelimb inflammation and snout alopecia were experienced by one maleanimal, and no significant mortality was recorded. The results showed a mild decline inlocomotive effects of mice served with 1 and 3 g/kg concentration of H. procumbens. Theblood glucose concentrations were lower in the treated mice than in the control group. Theoverview of this study suggests lower doses of Devil’s claw should be administered since itwill result in lower toxicity [106]. Furthermore, the consumption of medicinal plants mightinduce nephrotoxicity which results in a rapid decline in kidney function, for instance, theeffect of H. procumbens on renal function [107]. Bano et al. [108], reported no mortality andmorbidity in mice after oral administration of Devil’s claw to determine the acute toxicity.In another study, the pharmacokinetic parameters of harpagoside were assessed usingsingle-dose, two-treatment on six horses in a randomized cross-over design.

Moreover, H. procumbens plant extracts were regarded as unsafe in a study harpagosidethe main compound of Devil’s claw, was administrated to horses at 5 mg/kg and 10 mg/kgconcentrations. However, no clinical side effects were demonstrated [109].

Davari [110], established that a 600 mg/kg concentration of H. procumbens extractcauses necrosis in the kidney, liver, and lungs of fetuses of pregnant mice. Nonetheless,there were no changes in defects in body weight, structural malformations, and crown-rump length of treated embryos. The findings show the teratogenic potential, as well asthe histopathological alterations in fetal tissues [110]. Several clinical studies on the safetyas well as efficacy effects of H. procumbens were conducted in animals as well as humans(Tables 2 and 3). It is worth noting that Menghini and colleagues [11] have provided amountain of evidence supporting the therapeutic efficacy of H. procumbens preparation inboth preclinical and clinical studies.

Molecules 2022, 27, 3637 13 of 18

Table 2. Pre-clinical studies of Harpagophytum procumbens.

Disease/Study Aim Drug Formulation Participants/Animals Outcomes Reference

Neuropathic pain Plant extracts Rats Reduce pain [21]

Toxicity Plant extracts Rats Significant sex-related effectson blood chemistry [26]

Toxicity Devil’s claw capsules 20 mice Decrease in blood glucoselevel, weight gain in female [106]

neurotoxicity Capsules Rats anti-inflammatory activity andantioxidant effects [111]

Table 3. Clinical studies of Harpagophytum procumbens.

Disease/Study Aim Drug Formulation Participants/Animals Outcomes Reference

Knee Osteoarthritis Tablets Sixty human patients No significant difference butconsider to be safer. [97]

Gonarthritis Root extracts Ninety-two human patients Reduced gonarthritissymptoms [112]

4. Conclusions

Harpagophytum procumbens is a highly valued medicinal plant in southern Africa aswell as the entire world. The body of evidence has shown that Devil’s claw plants arerichly endowed with anti-cholesterolemic, antioxidant, anti-inflammatory, and pain killingeffects for the therapeutic treatment of countless diseases including rheumatoid arthritis,memory loss, lower back pain, osteoarthritis, lumbago, Syphilis, diabetes, indigestion,and heartburn, as well as acting as a detoxifying and tonic agent. Toxicological datahave shown that H. procumbens has adverse effects in high concentrations and variousmodels promote low dose levels as a safety parameter. Despite the massive body ofevidence of in vivo studies on the anti-inflammatory and analgesic activity of H. procumbens,alternative lines for future studies focus on animal and human models. Due to its popularity,Devil’s claw has been well-documented since the 1800 s, nonetheless, the research dataon the anti-inflammatory and analgesic activity of H. procumbens has reduced since the2000 s. However, this review has identified the decline in research data and promotesfurther investigation regarding the above. In order to streamline the future applicationof H. procumbens, more clinical studies are required to close the gap in research. Hence,providing increased therapeutic efficacy and safer H. procumbens products in the health andpharmaceutical sectors.

Author Contributions: N.G. and M.C.M. have collected research papers, written, conceptualized,reviewed, and edited the original draft. All authors have read and agreed to the published version ofthe manuscript.

Funding: This research received no external funding.

Acknowledgments: All authors acknowledge the Department of Biological and EnvironmentalSciences, Walter Sisulu University, Mthatha Campus (N.G. and M.C.M.).

Conflicts of Interest: All the authors declare no conflict of interest.

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